Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative
Jian Gao1, Minmin Fan1, Shuang Peng1
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Abstract:
Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca2+ from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity. The disruption of calcium homeostasis induced ER stress, leading to apoptosis. More importantly, the elevated intracellular calcium signals induced autophagy through the activation of the CaMKK-AMPK-mTOR pathway and mitochondrial damage. In two TNBC xenograft mouse models, RL71 also displayed strong efficacy including the inhibition of tumor growth, the reduction of metastasis, as well as the prolongation of survival time. These findings suggest SERCA2 as a previous unknown target candidate for TNBC treatment and support the idea that autophagy inducers could be useful as new therapeutics in TNBC treatment.
Insights
A novel small molecule, RL71, effectively targets sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) in triple-negative breast cancer (TNBC). This discovery offers a promising new therapeutic strategy for aggressive TNBC by inducing both apoptosis and autophagic cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) presents an aggressive phenotype with a poor prognosis.
- Metastatic progression and lack of targeted treatments contribute to TNBC's poor outcomes.
Purpose of the Study:
- To investigate the anti-cancer activity of small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) in TNBC.
- To elucidate the mechanisms underlying RL71-induced cell death in TNBC.
Main Methods:
- Utilized a small molecule RL71 to inhibit SERCA2 activity in TNBC cells.
- Assessed apoptosis and autophagic cell death induction.
- Investigated calcium homeostasis, endoplasmic reticulum (ER) stress, and mitochondrial damage.
- Evaluated RL71 efficacy in TNBC xenograft mouse models.
Main Results:
- RL71 demonstrated potent anti-cancer activity across all tested TNBC cells.
- RL71 induced both apoptosis and excessive autophagic cell death.
- Inhibition of SERCA2 by RL71 augmented cytosolic Ca2+ release, leading to ER stress and apoptosis.
- Elevated intracellular calcium triggered autophagy via the CaMKK-AMPK-mTOR pathway and mitochondrial damage.
- RL71 significantly inhibited tumor growth, reduced metastasis, and prolonged survival in TNBC xenograft models.
Conclusions:
- SERCA2 is identified as a novel therapeutic target for TNBC.
- Autophagy inducers represent a potential new class of therapeutics for TNBC treatment.
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